FIGURE 2.

Simplified illustration of a TSPO dimer, IMAC, and the mPTP complex on the mitochondrial membrane. TSPO is located on the outer mitochondrial membrane and facilitates cholesterol transport into the matrix. The close apposition of TSPO with IMAC and mPTP allows it to carry out its modulatory role in processes such as RIRR. During normal mitochondrial respiration, electrons which escape the ETC can combine with oxygen forming O^-₂ anions. ROS-scavenging enzymes work toward removing the ROS and hence keeping the cells healthy. Excessive production and/or defective scavenging of ROS under pathological conditions such as I/R and/or diabetes mellitus can activate ROS-sensitive IMAC, which amplifies ROS levels via RIRR. Escalating oxidative stress then activates the mPTP complex which can result in ΔΨ_m depolarization, leading to mitochondrial dysfunction, ischemic injury, and electrical remodeling paving way to arrhythmia. Additionally, internalized cholesterol can become oxidized by accumulating ROS, generating oxysterols which further enhance oxidative stress. The most common TSPO ligands 4′-chlorodiazepam (4′-Cl-DZP) and FGIN-1-27 have been used by many studies to study the involvement of TSPO in these processes.